US9890142B2 - PDE4 inhibitor - Google Patents

PDE4 inhibitor Download PDF

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Publication number
US9890142B2
US9890142B2 US14/903,707 US201414903707A US9890142B2 US 9890142 B2 US9890142 B2 US 9890142B2 US 201414903707 A US201414903707 A US 201414903707A US 9890142 B2 US9890142 B2 US 9890142B2
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group
chloro
benzoxazole
methylpiperazin
optionally substituted
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US20160159783A1 (en
Inventor
Chika Kikuchi
Yuji Tabata
Takeru Yamakawa
Takashi Matsuhira
Naoko Watanabe
Natsuki Kubota
Kaori Kaneda
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Meiji Seika Pharma Co Ltd
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Meiji Seika Pharma Co Ltd
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Assigned to MEIJI SEIKA PHARMA CO., LTD. reassignment MEIJI SEIKA PHARMA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MATSUHIRA, TAKASHI, KANEDA, KAORI, YAMAKAWA, TAKERU, WATANABE, NAOKO, KIKUCHI, CHIKA, KUBOTA, NATSUKI, TABATA, YUJI
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a PDE4 inhibitor.
  • PDE Phosphodiesterase
  • cAMP or cGMP cyclic nucleotides
  • PDE4 type 4 PDE
  • Non Patent Literature 1 Expert Opin. Investig. Drugs, 11, 1-13, 2002.
  • PDE4 inhibitors are known to be useful in the treatment of various inflammatory diseases in which TNF- ⁇ or the like is involved, because of suppressing the production or release of various cytokines, such as TNF- ⁇ , which play an important role in inflammation cascades (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002). Also, it has been reported that PDE4 inhibitors exhibit effects on not only inflammation in the respiratory system but also inflammation in the skin, and additionally, it has been reported that they also exhibit effects on mental illness (see Non Patent Literature 1: Expert Opin. Investig. Drugs, 11, 1-13, 2002).
  • Theophylline known as a PDE inhibitor has heretofore been used in the treatment of asthma (see Non Patent Literature 2: British Journal of Pharmacology, 155, 308-315, 2008).
  • roflumilast which is a potent PDE4 inhibitor, has been approved and used as a therapeutic drug for chronic obstructive pulmonary disease (COPD) in Europe and the United States (see Non Patent Literature 3: British Journal of Pharmacology, 163, 53-67, 2011), and additionally, the efficacy for interstitial pneumonia (idiopathic pulmonary fibrosis, etc.) in animal models has also been suggested (see Non Patent Literature 4: British Journal of Pharmacology, 156, 534-544, 2009).
  • Non Patent Literature 5 Amadeu G and Richard S. R., Expert Opin. Ther. Patents, August 2013, Vol. 23, No. 8, 997-1016.
  • clinical trials of PDE4 inhibitors for various inflammatory diseases have been carried out, and additionally, their possibilities for systemic lupus erythematosus have also been pointed out in nonclinical trials (see Non Patent Literature 1: Expert Opin. Investig.
  • Non Patent Literature 1 Expert Opin. Investig. Drugs, 11, 1-13, 2002, and Non Patent Literature 6: BMC Medicine, 11, 96, 2013).
  • Examples of diseases on which PDE4 inhibitors are likely to exhibit effects as described above include asthma, COPD, interstitial pneumonia, inflammatory bowel disease, Crohn's disease, multiple sclerosis, rheumatism, atopic dermatitis, psoriatic arthritis, psoriasis vulgaris, sarcoidosis, systemic lupus erythematosus, depression, learning and memory disorders, Parkinson's disease and Alzheimer's disease.
  • Patent Literature 1 JP 6-345744 A
  • Patent Literature 2 JP 10-29987 A
  • PDE4 inhibitors also include many compounds having emetogenicity, and concentration-dependent side effects such as vomiting and nausea have also been reported.
  • PDE4 inhibitors that can avoid these side effects have been demanded, and it is considered that such drugs may serve as excellent preventive or therapeutic agents for inflammatory diseases (respiratory diseases and skin diseases) and central nervous system diseases.
  • An object of the present invention is to provide a compound that has excellent PDE4 inhibitory activity and is useful as a pharmaceutical drug.
  • the present inventor has conducted diligent studies to attain the object and consequently completed the present invention by finding that a benzoxazole derivative having a piperazine ring, or a pharmacologically acceptable salt thereof has excellent PDE4 inhibitory activity.
  • the present invention provides:
  • R 1 , R 2 , R 3 and R 4 are each independently one group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocyclic or polycyclic aralkyl group, an optionally substituted 4- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-7 cycloalkyloxy group, an optionally substituted C 6-10 monocyclic or poly
  • R 5 and R 6 are each independently a hydrogen atom or a alkyl group
  • R 1 is a carboxy group
  • R 1 , R 2 , R 3 and R 4 are hydrogen atoms at the same time and the case where R 5 and R 6 are hydrogen atoms at the same time are excluded;
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • R 1 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 1-6 alkylthio group and an optionally substituted C 1-6 alkylsulfonyl group,
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
  • R 3 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted C 1-6 alkyloxy group, and
  • R 4 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocyclic or polycyclic aralkyl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted cycloalkyloxy group, an optionally substituted C 6-10 monocyclic or polycyclic aryloxy group, an optionally substituted 5- to 7-membered monocyclic heterocycl
  • R 1 , R 2 , R 3 and R 4 are each independently one group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocycle or polycyclic aralkyl group, an optionally substituted 4- to 10-membered monocycle or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-7 cycloalkyloxy group, an optionally substituted C 6-10 monocyclic or polycyclic
  • R 5 and R 6 are each independently a hydrogen atom or a C 1-6 alkyl group
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocycle heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocycle heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • R 1 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 1-6 alkylthio group and an optionally substituted C 1-6 alkylsulfonyl group,
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
  • R 3 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted C 1-6 alkyloxy group, and
  • R 4 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocycle or polycyclic aralkyl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-7 cycloalkyloxy group, an optionally substituted C 6-10 monocyclic or polycyclic aryloxy group, an optionally substituted 5- to 7-membered monocycle hetero
  • a PDE4 inhibitor comprising a compound represented by formula (1) or a pharmacologically acceptable salt thereof as an active ingredient:
  • R 1 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 1-6 alkylthio group and an optionally substituted C 1-6 alkylsulfonyl group,
  • R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,
  • R 3 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted C 1-6 alkyloxy group, and
  • R 4 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocycle or polycyclic aralkyl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-7 cycloalkyloxy group, an optionally substituted C 6-10 monocyclic or polycyclic aryloxy group, an optionally substituted 5- to 7-membered monocycle hetero
  • R 5 to R 8 are each independently a hydrogen atom or a C 1-6 alkyl group.
  • a PDE4 inhibitor comprising the compound or the pharmacologically acceptable salt thereof according to [4] as an active ingredient.
  • a pharmaceutical composition comprising the compound or the pharmacologically acceptable salt thereof according to any one of [1] to [4] as an active ingredient.
  • a pharmaceutical composition comprising the PDE4 inhibitor according to any one of [5] to [9] as an active ingredient.
  • a therapeutic agent for diseases caused by PDE4 comprising the compound or the pharmacologically acceptable salt thereof according to any one of [1] to [4] as an active ingredient.
  • a method for inhibiting PDE4, comprising administering the compound or the pharmacologically acceptable salt thereof according to any one of [1] to [4] to a patient.
  • [14] A method for treating diseases caused by PDE4, comprising administering the compound or the pharmacologically acceptable salt thereof according to any one of [1] to [4] to a patient.
  • the compound represented by formula (1) or the pharmacologically acceptable salt of the present invention has an excellent PDE4 inhibitory effect and is useful in the treatment or prevention of various diseases caused by PDE4.
  • diseases caused by PDE4 include asthma, chronic obstructive pulmonary disease (COPD), interstitial pneumonia, inflammatory bowel disease, Crohn's disease, multiple sclerosis, rheumatism, atopic dermatitis, psoriatic arthritis, psoriasis vulgaris, sarcoidosis, systemic lupus erythematosus, depression, learning and memory disorders, Parkinson's disease and Alzheimer's disease.
  • COPD chronic obstructive pulmonary disease
  • interstitial pneumonia inflammatory bowel disease
  • Crohn's disease multiple sclerosis
  • rheumatism atopic dermatitis
  • psoriatic arthritis psoriasis vulgaris
  • sarcoidosis systemic lupus erythematosus
  • depression learning and memory disorders
  • the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom and is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the C 1-6 alkyl group refers to a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isoamyl group and a n-hexyl group, and preferred is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group or an isobutyl group.
  • the C 3-7 cycloalkyl group refers to a cyclic alkyl group having 3 to 7 carbon atoms.
  • Examples of the C 3-7 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group, and preferred is a cyclopropyl group, a cyclopentyl group or a cyclohexyl group.
  • the C 6-10 monocyclic or polycyclic aryl group refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 10 carbon atoms.
  • Examples of the C 6-10 monocyclic or polycyclic aryl group include a phenyl group and a naphthyl group, and preferred is a phenyl group.
  • the C 7-11 monocyclic or polycyclic aralkyl group refers to an alkyl group having a monocyclic or polycyclic aromatic hydrocarbon group having 7 to 11 carbon atoms.
  • Examples of the C 7-11 monocyclic or polycyclic aralkyl group include a benzyl group and a naphthylmethyl group, and preferred is a benzyl group.
  • the 4- to 10-membered monocyclic or bicyclic heterocyclic group refers to a 4- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom.
  • Examples of the 4- to 10-membered monocyclic or bicyclic heterocyclic group include a tetrahydrofuranyl group, a pyrrolidyl group, a piperidyl group, an oxazolidinyl group, a morpholinyl group, a thienyl group, a furanyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a pyridyl group, a pyrimidyl group, an aziridinyl group, a tetrazolyl group, a quinolyl group and an isoquinolyl group, and preferred is a pyrrolidyl group, a morpholinyl group,
  • the di-C 1-6 alkylamino group refers to an amino group substituted by two C 1-6 alkyl groups mentioned above.
  • Examples of the di-C 1-6 alkylamino group include a dimethylamino group, a diethylamino group and a methylethylamino group, and preferred is a dimethylamino group or a diethylamino group.
  • the C 3-7 cycloalkylamino group refers to an amino group substituted by the C 3-7 cycloalkyl group mentioned above.
  • Examples of the C 3-7 cycloalkylamino group include a cyclobutylamino group, a cyclopentylamino group and a cyclohexylamino group, and preferred is a cyclopentylamino group.
  • the C 1-6 alkyloxy group refers to a group composed of an oxygen atom substituted by the C 1-6 alkyl group mentioned above.
  • Examples of the C 1-6 alkyloxy group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group and an isobutoxy group, and preferred is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group.
  • the C 3-7 cycloalkyloxy group refers to a group composed of an oxygen atom substituted by the C 3-7 cycloalkyl group mentioned above.
  • Examples of the C 3-7 cycloalkyloxy group include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group and a cyclohexyloxy group, and preferred is a cyclopentyloxy group or a cyclohexyloxy group.
  • the C 6-10 monocyclic or polycyclic aryloxy group refers to a group composed of an oxygen atom substituted by the C 6-10 monocycle or polycyclic aryl group mentioned above.
  • Examples of the C 6-10 monocycle or polycyclic aryloxy group include a phenyloxy group and a naphthyloxy group, and preferred is a phenyloxy group.
  • the C 7-11 monocyclic or polycyclic aralkyloxy group refers to a group composed of an oxygen atom substituted by the C 7-11 monocycle or polycyclic aralkyl group mentioned above.
  • Examples of the C 7-11 monocyclic or polycyclic aralkyloxy group include a benzyloxy group and a naphthylmethyloxy group, and preferred is a benzyloxy group.
  • the 4- to 10-membered monocycle or bicyclic heterocyclyloxy group refers to a group composed of an oxygen atom substituted by the 4 to 10-membered monocyclic or bicyclic heterocyclic group mentioned above.
  • Examples of the 4- to 10-membered monocyclic or bicyclic heterocyclyloxy group include a thiazolyloxy group and an oxazolyloxy group, and preferred is a thiazolyloxy group.
  • the C 1-6 alkylthio group refers to a group composed of a sulfur atom substituted by the C 1-6 alkyl group mentioned above.
  • Examples of the C 1-6 alkylthio group include a methylthio group, an ethylthio group, a propylthio group and an isopropylthio group, and preferred is a methylthio group.
  • the C 1-6 alkylsulfonyl group refers to a sulfonyl group substituted by the C 1-6 alkyl group mentioned above.
  • Examples of the C 1-6 alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group and a propylsulfonyl group, and preferred is a methylsulfonyl group.
  • the C 1-6 alkylcarbonyl group refers to a carbonyl group substituted by the C 1-6 alkyl group mentioned above.
  • Examples of the C 1-6 alkylcarbonyl group include an acetyl group, an ethylcarbonyl group, a propylcarbonyl group and a butylcarbonyl group, and preferred is an acetyl group.
  • the mono-C 1-6 alkylaminocarbonyl group refers to an aminocarbonyl group substituted by one C 1-6 alkyl group mentioned above.
  • Examples of the mono-C 1-6 alkylaminocarbonyl group include a methylaminocarbonyl group, an ethylaminocarbonyl group and a propylaminocarbonyl group, and preferred is a methylaminocarbonyl group or an ethylaminocarbonyl group.
  • the di-C 1-6 alkylaminocarbonyl group refers to an aminocarbonyl group substituted by two C 1-6 alkyl groups mentioned above.
  • Examples of the di-C 1-6 alkylaminocarbonyl group include a dimethylaminocarbonyl group, a diethylaminocarbonyl group and a dipropylaminocarbonyl group, and preferred is a dimethylaminocarbonyl group or a diethylaminocarbonyl group.
  • the C 1-6 alkyloxycarbonyl group refers to a carbonyl group substituted by the C 1-6 alkyloxy group mentioned above.
  • Examples of the C 1-6 alkyloxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group and an isopropoxycarbonyl group, and preferred is an ethoxycarbonyl group.
  • the hydroxyaminocarbonyl group refers to a carbonyl group substituted by an amino group substituted by a hydroxy group.
  • a substituent for the term “optionally substituted” can be any substituent as long as it is a group that can substitute each group, and each group may have one or more substituents.
  • the group that can substitute each group include a halogen atom, a cyano group, a hydroxy group, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a hydroxy-C 1-6 alkyl group, a C 1-6 alkyloxy group, an aminocarbonyl group, an oxo group, a nitro group, a C 1-6 alkylthio group, a C 1-6 alkylsulfonyl group and a C 6-10 aryl group.
  • the hydroxy-C 1-6 alkyl group refers to, for example, a C 1-6 alkyl group substituted by a hydroxy group and is, for example, a hydroxymethyl group.
  • examples of the C 1-6 alkyl group substituted by a fluorine atom include a trifluoromethyl group and a trifluoroethyl group
  • examples of the C 1-6 alkyloxy group substituted by a fluorine atom include a trifluoromethoxy group.
  • One embodiment of the present invention is a compound represented by formula (1) or a pharmacologically acceptable salt thereof:
  • the group represented by R 1 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 1-6 alkylthio group or an optionally substituted C 1-6 alkylsulfonyl group and is preferably a hydrogen atom, a fluorine atom, an iodine atom, a cyano group, a methyl group, a trifluoromethyl group, a cyclopropyl group, a phenyl group, a furanyl group, a pyrazolyl
  • the group represented by R 2 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group or an optionally substituted 5- to 7-membered monocycle heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom and is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a trifluoromethyl group, a pyrrolidyl group or a thienyl group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, a trifluoromethyl group or a thienyl group.
  • the group represented by R 3 is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an optionally substituted C 1-6 alkyl group or an optionally substituted C 1-6 alkyloxy group and is preferably a hydrogen atom, a fluorine atom, an iodine atom, a hydroxy group, a cyano group, a methyl group, a trifluoromethyl group or a methoxy group, more preferably a hydrogen atom, a fluorine atom, a cyano group or a methyl group.
  • the group represented by R 4 is a hydrogen atom, a halogen atom, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocyclic or polycyclic aralkyl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-7 cycloalkyloxy group, an optionally substituted C 6-10 monocyclic or polycyclic aryloxy group, an optionally substituted 5- to 7-membered monocyclic hetero
  • the groups represented by R 5 and R 6 are each independently a hydrogen atom or a C 1-6 alkyl group and are preferably a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a n-butyl group or an isobutyl group, more preferably a hydrogen atom or a methyl group.
  • the groups represented by R 7 and R 8 are each independently a hydrogen atom or a C 1-6 alkyl group and are preferably a hydrogen atom or a methyl group.
  • the compound represented by formula (1) or the pharmacologically acceptable salt thereof may be a compound represented by formula (1a) or a pharmacologically acceptable salt thereof
  • R 1 , R 2 , R 3 and R 4 are each independently one group selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxy group, a carboxy group, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted C 7-11 monocyclic or polycyclic aralkyl group, an optionally substituted 4- to 10-membered monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, a di-C 1-6 alkylamino group, an optionally substituted C 3-7 cycloalkylamino group, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 3-7 cycloalkyloxy group, an optionally substituted C 6
  • the compound represented by formula (1) or the pharmacologically acceptable salt thereof may be a compound represented by formula (1b) or a pharmacologically acceptable salt thereof.
  • R 1 , R 2 , R 3 and R 4 are each independently one group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a hydroxy group, a carboxy group, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a trifluoromethyl group, a hydroxymethyl group, a cyclohexylmethyl group, a methoxymethyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a phenyl group, a hydroxymethylphenyl group,
  • the compound represented by formula (1) or the pharmacologically acceptable salt thereof may be a compound represented by formula (1c) or a pharmacologically acceptable salt thereof:
  • R 1 , R 2 , R 3 and R 4 are each independently one group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, a methoxymethyl group, a trifluoromethyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, a hydroxymethylphenyl group, a fluorophenyl group, a pyrrolidyl group, a morpholinyl group, a thienyl group, a fluorothienyl group, a chlorothienyl group, a furanyl group, a pyrazolyl group, a methylpyrazo
  • R 2 should be one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and R 5 and R 6 should be each independently a hydrogen atom or a C 1-6 alkyl group.
  • R 2 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a trifluoromethyl group, a pyrrolidyl group and a thienyl group
  • R 5 and R 6 should be each independently one group selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, a n-butyl group and an isobutyl group.
  • R 2 should be one group selected from the group consisting of a fluorine atom, a chlorine atom, a cyano group, a methyl group, a trifluoromethyl, group and a thienyl group, and R 5 and R 6 should be each independently a hydrogen atom or a methyl group.
  • the compound represented by formula (1) or the pharmacologically acceptable salt thereof may be a compound represented by formula (1d) or a pharmacologically acceptable salt thereof:
  • R 1 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-7 cycloalkyl group, an optionally substituted C 6-10 monocyclic or polycyclic aryl group, an optionally substituted 5- to 7-membered monocyclic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, an optionally substituted C 1-6 alkyloxy group, an optionally substituted C 1-6 alkylthio group and an optionally substituted C 1-6 alkylsulfonyl group, R 2 is one group selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group and an optionally substituted 5- to 7-membered monocycle heterocyclic group containing 1 to 4 heteroatoms
  • R 1 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, an iodine atom, a cyano group, a methyl group, a trifluoromethyl group, a cyclopropyl group, a phenyl group, a furanyl group, a pyrazolyl group, a methoxy group, a trifluoromethoxy group, a methylthio group and a methylsulfonyl group
  • R 2 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a trifluoromethyl group, a pyrrolidyl group and a thienyl group
  • R 3 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, an iodine
  • R 1 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, an iodine atom, a cyano group, a methyl group, a trifluoromethyl group, a cyclopropyl group, a phenyl group, a furanyl group, a pyrazolyl group, a methoxy group, a trifluoromethoxy group, a methylthio group and a methylsulfonyl group
  • R 2 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a cyano group, a methyl group, a trifluoromethyl group and a thienyl group
  • R 3 should be one group selected from the group consisting of a hydrogen atom, a fluorine atom, a cyano group and a methyl group
  • R 4 should be one group selected from the group consisting of a hydrogen atom
  • Examples of the compound represented by formula (1) include the following compounds or salts thereof, though the present invention is not intended to be limited by these specific examples:
  • the compound represented by formula (1) of the present embodiment can be produced by various method, but can be produced by a typical method shown below.
  • a compound represented by formula (2) [wherein R 1 , R 2 , R 3 and R 4 have the same meanings as those in formula (1), also including preferable forms, and X is a leaving group such as a halogen atom, a thiol group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group or a phenoxy group] is reacted with a cyclic diamine represented by formula (3) [wherein R 5 , R 6 , R 7 and R 8 have the same meanings as those in formula (1), also including preferable forms, and Y is a protective group for the amino group] at 1 equivalent to 50 equivalents with respect to the molar number of the compound represented by formula (2) to obtain a compound represented by formula (4) [wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 have the same meanings as those in formula (1), also including preferable forms, and Y
  • a tert-butoxycarbonyl group or a benzyloxycarbonyl group described in “Protective Groups in Organic Synthesis” authored by T. W. Greene ((John Wiley and Sons, Inc.), 1991) can be used as the protective group for the amino group.
  • Dichloromethane, chloroform, benzene, toluene, xylene, tetrahydrofuran, diethyl ether, dimethoxyethane, N,N-dimethylformamide, dimethyl sulfoxide or the like can be used as a solvent used in the production method.
  • the reaction temperature is selected from the range of ⁇ 50 to 200° C., preferably 0 to 150° C.
  • the reaction time is in the range of 5 minutes to 48 hours, preferably 30 minutes to 20 hours.
  • an additive for example, triethylamine or N,N-diisopropylethylamine
  • an additive for example, triethylamine or N,N-diisopropylethylamine
  • the compound represented by formula (4) produced by this method may be derivatized into another compound that falls within the scope of the present invention by subjecting each substituent (R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 ) to functional group conversion.
  • substituents include the introduction of a functional group by various coupling reactions or the like using a metal catalyst.
  • Typical examples of the coupling reactions include Kumada-Tamao-Corriu coupling, Migita-Kosugi-Stille coupling, Suzuki-Miyaura coupling, Negishi coupling and Buchwald-Hartwig coupling.
  • the compound represented by formula (1) of the present embodiment can exist in the form of an acid-addition salt in addition to the form of a free base.
  • the acid-addition salt include: salts of hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; salts of inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, perchloric acid and carbonic acid; salts of organic carboxylic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lactic acid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, maleic acid, propionic acid, formic acid and malic acid; salts of acidic amino acids such as aspartic acid and glutamic acid; salts of alkylsulfonic acids such as methanesulfonic acid; and salts of arylsulfonic acids
  • the compound represented by formula (1) of the present embodiment may have one or two or more asymmetric carbon atoms according to the type of a substituent, optically active forms and diastereomers based on the one or two or more asymmetric carbon atoms, arbitrary mixtures thereof, racemates and the like are all included in the scope of the present invention. Moreover, corresponding hydrates or solvents are also included in the compound represented by formula (1) of the present invention or the pharmacologically acceptable salt thereof. Examples of the solvates include isopropanol solvates.
  • the compound represented by formula (1) of the present embodiment can be used as a PDE4 inhibitor.
  • An alternative embodiment of the present invention is a pharmaceutical composition comprising the compound represented by formula (1) or the pharmacologically acceptable salt thereof as an active ingredient.
  • the pharmaceutical composition of the present embodiment permits any of oral and parenteral administration routes and can be administered to a human or a non-human animal.
  • the pharmaceutical composition comprising the compound represented by formula (1) of the present embodiment or the pharmacologically acceptable salt thereof as an active ingredient is prepared into an appropriate dosage form according to an administration route.
  • Examples of the pharmaceutical composition specifically include: oral formulations such as tablets, pills, capsules, granules, powders, elixirs, suspensions, emulsions and syrups; and parenteral formulations such as injections, inhalants, formulations for rectal administrations, suppositories, lotions, sprays, ointments, creams and patches.
  • oral formulations such as tablets, pills, capsules, granules, powders, elixirs, suspensions, emulsions and syrups
  • parenteral formulations such as injections, inhalants, formulations for rectal administrations, suppositories, lotions, sprays, ointments, creams and patches.
  • compositions can be manufactured by conventional methods using an excipient, a disintegrant, a binder, a lubricant, a colorant and the like usually used in the pharmaceutical field.
  • the content of the compound represented by formula (1) or the pharmacologically acceptable salt thereof in the pharmaceutical composition of the present embodiment differs depending on its dosage form and is usually 0.01 to 50% by mass, preferably 0.05 to 20% by mass, with respect to the total mass of the pharmaceutical composition in terms of a free form.
  • the dosage form is appropriately determined according to each individual case in consideration of the age, body weight, and sex of a patient, difference in disease, the degree of symptoms, etc., and is usually 0.1 to 1000 mg, preferably 1 to 300 mg, per day in an adult, which is administered once a day or in several divided portions per day.
  • the obtained crude product was purified by silica gel column chromatography (developing solvent, chloroform) to obtain 1.88 g of a mixture of 2-bromo-4-chloro-5-(trifluoromethyl)phenol and 2-bromo-4-chloro-3-(trifluoromethyl)phenol.
  • the obtained mixture (826 mg) was dissolved in acetic acid (3.0 mL), then 70% nitric acid (380 ⁇ L) was added thereto under ice cooling, and the resulting mixture was stirred for 1 hour in this state. After that, the resulting mixture was stirred at room temperature for 1 hour, then water was added thereto, and the product was extracted with ethyl acetate.
  • the title compound was obtained in a similar manner as in Reference Example 1(d) except that a mixture of 2-amino-6-bromo-4-fluoro-3-(trifluoromethyl)phenol and 6-amino-2-bromo-4-fluoro-3-(trifluoromethyl)phenol obtained in Reference Example 19(b) was used instead of 2-amino-4-chloro-6-isopropylphenol.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(furan-3-yl)benzoxazol-2-yl)-3-methyl piperazine obtained in Example 17(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 16(b) The title compound was obtained in a similar manner as in Example 16(b) except that 2-thiophene boronic acid was used instead of 3-thiophene boronic acid.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(thiophen-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 18(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 16(b) The title compound was obtained in a similar manner as in Example 16(b) except that phenylboronic acid was used instead of 3-thiophene boronic acid.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-phenylbenzoxazol-2-yl)-3-methylpiperazine obtained in Example 19(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(pyrrolidin-1-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 20(a) was used instead of (S)-1-tert-butoxycarbonyl-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 20(a) The title compound was obtained in a similar manner as in Example 20(a) except that morpholine was used instead of pyrrolidine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(morpholin-1-yl)benzoxazol-2-yl)-3-m ethylpiperazine obtained in Example 21(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(piperidin-1-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 22(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(furan-2-yl)benzoxazol-2-yl)-3-methyl piperazine obtained in Example 23(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(cyclopentylamino)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 24(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 20(a) The title compound was obtained in a similar manner as in Example 20(a) except that diethylamine was used instead of pyrrolidine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-(5-chloro-7-(diethylamino)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 25(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 20(a) The title compound was obtained in a similar manner as in Example 20(a) except that dimethylamine was used instead of pyrrolidine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(dimethylamino)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 26(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-cyclopropylbenzoxazol-2-yl)-3-meth ylpiperazine obtained in Example 27(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) 2.2 mg of the title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(cyclopentyloxy)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 28(a) (10.4 mg) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 28(a) The title compound was obtained in a similar manner as in Example 28(a) except that ethanol was used instead of cyclopentyl alcohol.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-ethoxybenzoxazol-2-yl)-3-methylpiperazine obtained in Example 29(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 28(a) The title compound was obtained in a similar manner as in Example 28(a) except that 1-propanol was used instead of cyclopentyl alcohol.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-n-propoxybenzoxazol-2-yl)-3-methylpiperazine obtained in Example 30(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-cyclopentylbenzoxazol-2-yl)-3-methylpiperazine obtained in Example 31(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 31(a) The title compound was obtained in a similar manner as in Example 31(a) except that n-butyl zinc bromide (a 0.5 M solution in THF) was used instead of cyclopentyl zinc bromide (a 0.5 M solution in toluene).
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(1H-pyrazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 33(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(oxazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 34(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 2-(tributylstannyl)thiazole was used instead of 2-(tributylstannyl)oxazole.
  • Example 33(a) The title compound was obtained in a similar manner as in Example 33(a) except that imidazole was used instead of pyrazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(1H-imidazol-1-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 36(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 4-(tributylstannyl)thiazole was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiazol-4-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 37(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 5-(tributylstannyl)thiazole was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiazol-5-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 38(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-methylfuran-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 39(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 33(a) The title compound was obtained in a similar manner as in Example 33(a) except that 4-methylpyrazole was used instead of pyrazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(4-methyl-1H-pyrazol-1-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 40(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 2-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(pyridin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 41(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(pyridin-3-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 42(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 42(a) The title compound was obtained in a similar manner as in Example 42(a) except that 4-pyridyl boronic acid MIDA ester was used instead of 3-pyridyl boronic acid MIDA ester.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(pyridin-4-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 43(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 31(a) 58.9 mg of the title compound was obtained in a similar manner as in Example 31(a) except that cyclohexyl zinc bromide (a 0.5 M solution in THF) was used instead of cyclopentyl zinc bromide (a 0.5 M solution in toluene).
  • Example 16(c) 4.0 mg of the title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-cyclohexylbenzoxazol-2-yl)-3-methylpiperazine obtained in Example 44(a) (58.9 mg) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(2H-1,2,3-triazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 45(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 45(a) The title compound was obtained in a similar manner as in Example 45(a) except that 1,2,4-triazole was used instead of 1,2,3-triazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(1H-1,2,4-triazol-1-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 46(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 31(a) The title compound was obtained in a similar manner as in Example 31(a) except that isobutyl zinc bromide (a 0.5 M solution in THF) was used instead of cyclopentyl zinc bromide (a 0.5 M solution in toluene).
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-isobutylbenzoxazole-2-yl)-3-methylpiperazine obtained in Example 47(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(b) The title compound was obtained in a similar manner as in Example 16(b) except that o-hydroxymethylphenyl boronic acid was used instead of 3-thiophene boronic acid.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(2-hydroxymethylphenyl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 48(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • N-Methylimidazole 44 ⁇ L, 1.0 mmol was dissolved in diethyl ether (1.0 mL), then resulting mixture was cooled to ⁇ 78° C., and n-butyllithium (a 2.77 M solution in hexane, 542 ⁇ L, 1.5 mmol) was added thereto, and the resulting mixture was stirred for 1 hour in this state.
  • Tributylstannyl chloride (405 ⁇ L, 1.5 mmol) was added to the reaction mixture, the temperature of the reaction mixture was gradually raised, and the mixture was further stirred at room temperature for 1 hour.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(1-methyl-1H-imidazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 49(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(1H-imidazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 50(b) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 28(a) The title compound was obtained in a similar manner as in Example 28(a) except that water was used instead of cyclopentyl alcohol.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(cyclohexyloxy)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 52(b) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(cyclopropylmethoxy)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 53(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 50(b) The title compound was obtained in a similar manner as in Example 50(b) except that 3-bromoisothiazole was used instead of 2-bromo-1H-imidazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(isothiazole-3-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 54(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 50(b) The title compound was obtained in a similar manner as in Example 50(b) except that 2-bromothiazole-5-methanol was used instead of 2-bromo-1H-imidazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-hydroxymethylthiazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 55(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 2-(tributylstannyl)pyrimidine was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(pyrimidin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 56(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(b) The title compound was obtained in a similar manner as in Example 16(b) except that 5-chloro-2-thiophene boronic acid was used instead of 3-thiophene boronic acid.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-chlorothiophen-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 57(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 5-chloro-2-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-chloropyridin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 58(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 4-chloro-2-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(4-chloropyridin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 59(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 6-fluoro-2-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(6-fluoropyridin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 60(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 34(a) The title compound was obtained in a similar manner as in Example 34(a) except that 3-fluoro-2-(tributylstannyl)pyridine was used instead of 2-(tributylstannyl)oxazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(3-fluoropyridin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 61(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 50(b) The title compound was obtained in a similar manner as in Example 50(b) except that 2-bromo-5-cyanothiazole was used instead of 2-bromo-1H-imidazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-cyanothiazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 62(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-methylthiazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 63(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 16(b) The title compound was obtained in a similar manner as in Example 16(b) except that 2-chloro-3-thiophene boronic acid was used instead of 3-thiophene boronic acid.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(2-chlorothiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 64(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 50(b) The title compound was obtained in a similar manner as in Example 50(b) except that 2-bromo-5-carbamoylthiazole was used instead of 2-bromo-1H-imidazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(5-carbamoylthiazol-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 65(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-methylpiperazine.
  • Example 50(b) The title compound was obtained in a similar manner as in Example 50(b) except that 2-bromo-3-cyanopyridine was used instead of 2-bromo-1H-imidazole.
  • Example 16(c) The title compound was obtained in a similar manner as in Example 16(c) except that (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(3-cyanopyridin-2-yl)benzoxazol-2-yl)-3-methylpiperazine obtained in Example 66(a) was used instead of (S)-1-tert-butoxycarbonyl-4-(5-chloro-7-(thiophen-3-yl)benzoxazol-2-yl)-3-m ethylpiperazine.

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EP3936192A4 (en) 2019-03-06 2022-11-16 Daiichi Sankyo Company, Limited PYRROLOPYRAZOL DERIVATIVES
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